title: Arginyltransferase regulates alpha cardiac actin function, myofibril formation and contractility during heart development.
abstract: Post-translational arginylation mediated by arginyltransferase (Ate1) is essential for cardiovascular development and angiogenesis in mammals and directly affects myocardium structure in the developing heart. We recently showed that arginylation exerts a number of intracellular effects by modifying proteins involved in the functioning of the actin cytoskeleton and in cell motility. Here, we investigated the role of arginylation in the development and function of cardiac myocytes and their actin-containing structures during embryogenesis. Biochemical and mass spectrometry analyses showed that alpha cardiac actin undergoes arginylation at four sites during development. Ultrastructural analysis of the myofibrils in wild-type and Ate1 knockout mouse hearts showed that the absence of arginylation results in defects in myofibril structure that delay their development and affect the continuity of myofibrils throughout the heart, predicting defects in cardiac contractility. Comparison of cardiac myocytes derived from wild-type and Ate1 knockout mouse embryos revealed that the absence of arginylation results in abnormal beating patterns. Our results demonstrate cell-autonomous cardiac myocyte defects in arginylation knockout mice that lead to severe congenital abnormalities similar to those observed in human disease, and outline a new function of arginylation in the regulation of the actin cytoskeleton in cardiac myocytes.
authors.affiliation: Department of Animal Biology and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Reena
authors.initials: R
authors.lastname: Rai
authors.forename: Catherine C L
authors.initials: CC
authors.lastname: Wong
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.forename: N Adrian
authors.initials: NA
authors.lastname: Leu
authors.forename: Dawei W
authors.initials: DW
authors.lastname: Dong
authors.forename: Caiying
authors.initials: C
authors.lastname: Guo
authors.forename: K John
authors.initials: KJ
authors.lastname: McLaughlin
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Anna
authors.initials: A
authors.lastname: Kashina
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D019881:Aminoacyltransferases / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000378:metabolism; D002478:Cells, Cultured; D006321:Heart / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D009210:Myofibrils / Q000201:enzymology* / Q000473:pathology / Q000648:ultrastructure; D017433:Protein Structure, Secondary; D012518:Sarcomeres / Q000473:pathology / Q000648:ultrastructure
chemical_list: D000199:Actins; D001120:Arginine; D019881:Aminoacyltransferases; C019727:arginyltransferase